Gastro Block Flashcards
What is the arrangment of a Liver lobule? What vessels are there?
Organisation of hepatocytes into lobules à stacks of the plates of the cells, around a central vein (C).
At the junction of L’s = Portal Triads. (T)
- Branch of hepatic portal vein (PV) = deoxyblood from gut.
- Branch of hepatic artery (A) = oxygenated blood.
- Bile Duct (B)
Give rise to network of Sinusoids.
Basic Structure of a Heptacyte?
Polyhedral = 6 surfaces
1-2 nuclei many cells are tetraploid or polyploidy
Lots of Protein syn = Prominent rough ER, Golig complexes and secretory vesicles.
Fat Metabolism = prominent smooth ER
Lots of mitochondria
Supported by reticular fibres (collagen type III)
How do Hepatocyte regenerate and what can inhibit this process?
Replaced by division of existing hepatocytes (tightly regulated)
Ability to divide can be damaged by Hep B, C, alcohol abuse (cirrhosis and atophy). Ok after Hep A
Describe Zonation of Hepatic Acinus?
Oxygen, toxins and metabolites/nutrients
1: high in O2, toxins and nutrients
3: low in O2, toxins and metabolites (closest to central vein)
Where is Bile made? Main component and function? Where does it flow to?
Produced in hepatocytes
Mainly Bile Salts
Surfactnas that emulsify fat and aid lipid digestion
Synthesised from cholesterol
Resorbed in SI and recycled
Flow outwards through channels between HP to bile ducts at triads.
Steps of Heme Metablism?
Macrophages phagocytose old RBC and split into globin and heme.
Cleavage of heme ring by Heme oxygenase gives free Fe2+ (travels by transferrin in blood) and Biliverdin à reduced to Bilirubin in cells.
Bilirubin enters circulation in binds reversibly to albumin and carried to liver, uptake by Hepatocyte across basal lateral membrane (active).
Bilirubin then conjugated with glucuronic acid residues at ER à Bilirubin mono/diglucuronide (more soluble but still cannot be absorbed by biliary or intestinal epithelia).
Once Bilirubin is conjugated in Liver how is it excreted?
Exported to Bile à into digestive tract and excreted
Some converted back to bilirubin by bacteria in terminal ileum and colon and then to Urobilinogen
Can enter plasma and filtered by kidney to urobilin and excreted
Stay in colon and converted to stercobilin which is main pigment of faeces and then excreted.
Define Jaundice?
Accumulation of bilirubin in extracellular fluid in either free or conjugate form
What are the three types of functional units of the Liver?
- Classic hepatic lobule = drains blood from portal vein and artery to hepatic or central vein.
- Portal lobule = drains bile from hepatocytes to network of anastomosing network of bile ducts à eventually into duodenum through single large common bile duct.
- Portal acinus = supplies oxygenated blood to hepatocytes.
Where to hepatitis viruses replicate? And how is most of damage caused?
in hepatocytes, non cytolytic cycle, damged caused by immune reaction
How is age related to outcomes in Hepatitis infections?
Exposure in early life less severe acute disease but higher rates of chronic infection.
Describe Hepatitis A life-cycle:
Initial site of replication: intestinal epithelia –> Blood (Transient Viremia)-> Primary site of replication in hepatocytes cytoplasm –> bile & faeces.
Which Hep Virus is Faecal oral route and Percutaneous, permucosal transmission?
A&E = Faaecal oral route
B,C and D = Percutaneous permucosal (eg Sexual, IV drug use)
Hep B = Perinatal
Life cycle of HBV, HDV and HCV?
Chronic
Exchange of blood, semen and secretions -> Penetration of mucosal epithelia -> blood -> replication in liver (one site only) -> Blood derived products -> injections etc -> transmission
Incubation periods for Hep
A
B
C
D
E
A: 2-4 weeks
B: 6 weeks to 6 months
C: 2 months
D: 2wks to 3 months
E: 6 wks to 2 months
Current HBV anti viral drugs and prevention?
IFN-a -> response rate 30-40% horrible drug.
Nucleoside analogues: targets bcz of reverse transcription. eg Lamivudine.
Won’t clear virus à relapse due to mutation in virus.
New generation drugs: target entry receptor protein NCTP.
3 – inactivated subviral particles = vaccine also protects against HDV.
Diagnosising Viral Hep A using Serlogie?
ELISA for serological
- IgM antibody to viral proteins (acute)
- IgG antibody to viral proteins either vaccine or rising titre confirms infection
Two ways Hep b and D can infect together and their outcomes?
Hep B and D:
Coinfection (same time) = severe acute disease, low risk of chronic infection
Superinfection (HDV infection on Chronic Hep B infection): Chronic HDV infection high risk of liver disease
Course of antigens and antibody levels in acute vs chronic infection of Hep B?
Acute:
Surface antigen Peak at 12 weeks -> reduce as infection cleared
IgM anti-HBcore antibody peak at about 12 weeks = peak symptoms
IgG anti-HBcore peaks and level is maintined post clearance
anti-HBsurface -> levels off after infection = recovery and vaccination.
Chronic
HBsurface antigen peaks and is maintained but no antibodes to HBs
Peak of IgM anti-HBc then sustained total anti-HBcore antibodies
Which Hepititis’ are associated with Cancer?
B and C heptacellular carcinoma = most common cause of liver cancer
Signs, Symptoms and Biochem tests of Hepatitis?
Symptoms: nausea, anorexia, malaise
Signs: enlarged liver, Jaudice (after 1 week of symptoms)
Biochem: elevated bilirubin, ALT & AST (high in early disease liver cell necrosis)
Coagulation tests: prothrombin time may become abnormal.
Hep C treatment?
INF-A and Ribavirin target broadly = ineffective.
Direct acting antiviral (DAA) = new. Specific life cycle inhibitors:
Viral entry, RNA translation & replication, Viral ntry, assembly and release. Several highly curative short duration therapies eg Sofosbuvir and Simeprevir.
Sequele of Chronic Hep Infections?
Mostly mediated by immune response leading to cell damage
Cirrhosis, liver failure and liver cancer
Colour of faeces and urine in the three types of Jaundice?
Pre-Hepatic:
normal urine (uc-bilirubin can’t be excreted) and dark brown faeces (increased stercobilinogen
Hepatic:
Dark coloured urine (exretion of c-bilirubin), normal coloured faeces.
Post Hepatic
Dark brown urine (exretion of c-bilirubin) & pale/clay faeces (low stercobilinogen in GI)
Basic Mechanism of Post, Pre and Hepatic Jaundice?
Pre-Hepatic Jaundice:
Increased levels of bilirubin often from RBC destruction that the liver is unable to cope with.
Hepatic Jaundice:
Hepaococyte disfunction in the liver (often due to alcohol or viral damage) poor uptake, conjugation or release of bilirubin into bile ducts.
Pre Hepatic Jaundice:
Due to obstruction of portal hepatic system or bile ducts so conjugated bilirubin gets backed up.
Liver enzyme levels in types of Jaundice?
Pre: Normal
Hepatic: elevated AST, ALP and ALT
AST>1000 indicate actue viral hep
AST >2x ALT = alcohol
Hepatocellular damage ALT 3x ALP
Post: marked ALP elevation
6 main functions of the Liver?
Carbohydrate metabolism (Gluconeogenisis, glycolysis, glycogen snthesis)
Fat metabolism (Liponeogenesis)
Protein Metabolism (ketogenesis)
Bile synthesis
Storage (glycogen, iron, fat soluable vitamins)
Detoxification (drugs, nitrogenous, steroid hormones)
Four main patholgoical responses that liver has to diease? And basic cause?
- Cholestasis and obstructive jaundice
blockage to either intrahepatic or extrahepatic bile ducts
- Acute hepatitis
When diseases cause necrosis of liver cells with assoc inflammation, several causes main being viral and toxic damge
- Chronic hepatitis
Continued hepatic inflammation > 6 months à viral and immune mediated.
Can develop to hepatic fibrosis
4. Cirrhosis
Results from long standing fibrosis.
Extensive scarring and nodules of regenerated liver
Architecture leads to increase back pressure and portal hypertension.
What are the steps of Alcohol Oxidation in the lIver by ADH and ALDH?
What are the by products?
Features of a bolus administration of a drug?
What does the curve of the concentration of the durg in blood look like?
- rapid rise
- Drug has constant half life = measurement of perisistence in body
- Peak concentration = Dose of druge/ volume of distribution
- amount of drug in body falls expontially with time
Features of a short term i.v infusion and it’s [drug] curve?
Why would you use this instead of bolus?
- concentration rises in a parabola as elimination happens at a faster rate as [drug] increases - flattens out.
- peak concentration not as high as i.v bolus for same amount of drug.
- After infusion get simple first order elmination
- useful in drugs with narrow thearpeutic window or index eg gentamicin
Long term i.v infusion features?
How does graph look?
Continuous infusion until equilibrium is reached
At steady state: rate of infusion = rate of elimination
Conc of steady state proportional to infusion rate makes it easy to dial up to a particular concentration
In multiple dosing how does half life related to variations in plasma concentrations?
If a drug is given 3 times a day what is its probable half life?
If you dose every half life you get a two fold variation in concentration in plasma
This variation is normally tolerated by drugs
With meals drugs = half life of 8 hrs
Describe the graph for oral administration:
compare to iv adminsitration
- peak not as high as iv admin
- as not all drug might be absorbed
- under go first pass metabolism
- Rate of change of drug in body related to absorption rate in SI and the elimination rate either through metabolism or by kidney (from plasma)
How do you calculate Bioavailability from a curve?
If BA of a drug orally is 75% and you would normally give a iv dose of 100mg how much should you give orally?
Need to administer 100 x 0.75 = 133 mg to ge the same effect as at 100mg iv dose.
Describe the main features of a rapid iv admin of a slowly disributing drug?
- inital peak concentration is higher (as smaller volume of distribution then predicted initialy)
- Elimination is slower as there is an equilibirum between central and peripheral stores as drug is ejected from body.
What are the features of rapid iv admin of a zero order (saturable) elimination drug?
- process of elmination (often an enzyme involved in metabolism) gets saturated and elimination becomes constant aka not dependent on drug concentration (exponetial).
- not a problem with single dosing
- with multi dosing don’t reach steady state concentration instead drug accumulates
- also small changes in dosing = large changes in drug concentrations.
